ENHANCEMENT OF GABA(A) RECEPTOR-MEDIATED CONDUCTANCES INDUCED BY NERVE INJURY IN A SUBCLASS OF SENSORY NEURONS

1. The effects of axotomy on the electrophysiologic properties of adul t rat dorsal root ganglion (DRG) neurons were studied to understand th e changes in excitability induced by traumatic nerve injury. Nerve inj ury was induced in vivo by sciatic nerve ligation with distal nerve tr ansection. Two to four weeks after nerve ligation, a time when a neuro ma forms, lumbar (L4 and L5) DRG neurons were removed and placed in sh ort-term tissue culture. Whole cell patch-clamp recordings were made 5 -24 h after plating. 2. DRG neurons were grouped into large (43-65 mu m)-, medium (34-42 mu m)-, and small (20-32 mu m)- sized classes. Larg e neurons had short duration action potentials with similar to 60% hav ing inflections on the falling phase of their action potentials. In co ntrast, action potentials of medium and small neurons were longer in d uration and similar to 68% had inflections. 3. Pressure microejection of gamma-aminobutyric acid (GABA, 100 mu M) or muscimol (100 mu M) Ont o voltage-clamped DRG neurons elicited a rapidly desensitizing inward current that was blocked by 200 mu M bicuculline. To measure the peak conductance induced by GABA or muscimol, neurons were voltage-clamped at a holding potential of -60 mV, and pulses to -80 mV and -100 mV wer e applied at a rate of 2.5 or 5 Hz during drug application. Slope cond uctances were calculated from plots of whole cell current measured at each of these potentials. 4. GABA-induced currents and conductances of control DRG neurons increased progressively with cell diameter. The m ean GABA conductance was 36 +/- 10 nS (mean +/- SE) in small neurons, 124 +/- 21 nS in medium neurons, and 527 +/- 65 nS in large neurons. 5 . After axotomy, medium neurons had significantly larger GABA-induced coductances compared with medium control neurons (390 +/- 50 vs. 124 /- 21; P < 0.001). The increase in GABA consuctance of medium neurons was associated with a decrease in duration of action potentials. In co ntrast, small neurons had no hange in GABA consuctance or action poten tial duration after ligation. The GABA conductane of large control neu rons was highly variable, and ligation resulted in an increase that wa s significantly only for neurons > 50 mu m. The mean action potential duration in large neurons was not significantly changed, but neurons w ith inflections on the falling phase of the action potential were less common after ligation. There was no difference in resting potential o r input resistance between control and ligated groups, except that the resting potential was less negative in small cells after axotomy. 6. Histograms of neuronal diameter distributions were constructed for con trol and ligated groups. The cell diameter distribution of control and ligated neurons were similar, but the ligated group had a decrease in the proportion of large neurons and a 27% increase in medium neurons, with no changein the relative proportion of other size classes. The 2 7% increase in the number of medium neurons was unlikely to be solely responsible for the 314% increase in GABA conductance seen in medium n eurons after ligation, although some of the observed change could be a ttributed to a shift of large neurons (and their associated electrophy siologic properties) into the medium group. 7. These results indicate that axotomy resulted in a significant increase in GABA(A) receptor-me diated conductance in specific size classes of sensory neurons. We hyp othesize that this selective increase in GABA conductance results from an injury-induced increase in the density of GABA(A) receptors on the soma or a change in the expression of specific GABA(A) receptor subty pes with different single channel conductances.